Histamine has a pivotal role in a variety of in vivo reactions. Endogenous histamine plays an important role in regulating cell proliferation in normal and neoplastic cells. Increased histamine biosynthesis and content has been reported in different human and experimental neoplasias (Cricco et al., Agents and Actions, 43:17 (1994); Garcia-Caballero et al., Agents and Actions, 27:227 (1989); Scolnik et al., Trends Pharmacol. Sci., 6:357 (1985)). Using histamine receptor antagonists, in vitro and in vivo experiments (Van der Ven et al., Br. J. Cancer, 68:475 (1990); Watson et al., Gut, 34:1091 (1993)) have demonstrated that histamine acts through the specific histamine membrane receptors, H1, H2 and H3, and may regulate tumor growth and development (Cricco et al., Agents and Actions, 38:175 (1993)). However, the most compelling evidence supporting a central role for histamine in neoplasia are the results of clinical trials showing increased survival of gastric cancer patients after treatment with cimetidine, an H2 receptor antagonist (Tonnesen et al., Lancet, ii:990 (1988); Burtin et al., Eur. J. Cancer Clin. Oncol., 24:161 (1988)). In addition to promoting proliferation of tumor cells, histamine also has potent immunosuppressive effects which can favor tumor cell growth, for example by blunting NK activity (Hellstrand et al., Scand. J. Immunol, 34:741 (1991)) and by activating T-suppressor cell function (Bartholeyns et al., Trends Pharmacol. Sci., 7:23 (1985)).
Histamine levels in cells and tissues are regulated by histidine decarboxylase (HDC), the only enzyme that catalyzes the formation of histamine from L-histidine. Thus, HDC is both a specific marker for histamine and an early indicator of histamine-mediated proliferation and immune suppression. Increased HDC activity has been measured in human colorectal tumor specimens (Garcia-Caballero et al., Agents and Actions, 23:357 (1988)). Moreover, the inhibitory effects of .alpha.-fluoromethyl-histidine, a suicide inhibitor of HDC (Watanabe et al., Trends Pharmacol. Sci., 11:363 (1990)), have been demonstrated in tumor models (Bartholeyns et al., Cancer Res., 44:639 (1984); Brandes et al., Agents and Actions, 33 (Suppl.):325 (1991)).
Although anfibodies to HDC have been developed, the first such antibody was a preparation of polyclonal antibodies of limited use due to its species specificity, i.e., the polyclonal antibodies proved useful only for rat studies (Watanabe et al., Neurosci. Lett., 39:249 (1983); Taguchi et al., Brain Res., 340:235 (1985)). Yatsunami and colleagues reported the generation of a HDC monoclonal antibody (mAb), using a peptide sequence conserved across human and rat HDC (J. Biol Chem., 270:30813 (1995)). However, this antibody recognized only denatured HDC.
Thus, a need exists for antibodies to HDC which are useful to detect HDC in tissue specimens, e.g., antibodies which recognize native human HDC in tumor biopsies.